Abstract

Radiotherapy is a cornerstone of modern integrated cancer care. It combines the real human face of caring for people with cancer with extraordinary science and technology. Its history is rich and our modern specialty of radiation oncology is built on the shoulders of giants, both in technology and biology. It is a highly cost-effective treatment that stands proudly on a large and robust evidence base. Quality radiation treatment can add significantly to the chance of curing many people with cancer and remains an invaluable palliative treatment for others. About half of all cancer patients benefit from having radiotherapy, mostly through improved survival. The specialty and what it can bring to patients continues to evolve apace and the high quality of treatment delivery is critical to its success.

Radiation treatment has evolved over the past 12 decades into a highly sophisticated, cost-effective cornerstone treatment for people with cancer. It adds significantly to the chance of cure for many people with cancer and can be very effective in helping relieve symptoms for those in whom cure is not possible. Since 1956, when linear accelerators (linacs) came into mainstream clinical use in Australia, radiotherapy technology has advanced greatly. This, accompanied by major advances in our understanding of the biology of cancer and radiobiology, and exploitation of the benefits of combined modality treatment with surgery and systemic therapies, has led to significant improvements in treatment outcomes. Although we have described the developments separately, often we see advances in technology, biology and integration occurring simultaneously and scattered across the globe.

The primary goal of radiation treatment delivery for cancer is, always has been and always will be to maximally treat cancer tissue and maximally spare normal tissue. This underlying philosophy has guided almost all of the developments in radiation oncology from the outset. The desire to treat our patients’ cancer to the required dose, while reducing collateral damage, drives our modern technology and the delivery of radiotherapy. With advances in technology, we can now shape beams with very steep dose gradients, delivering high doses to cancer tissue while sparing the adjacent healthy organ(s). This requires a deep understanding of anatomical and molecular imaging, tumour and normal tissue biology and treatment related risk factors in order to define the tissues to be treated, the dose to be delivered and the organs to be spared or dose limited. The integration of radiotherapy with other treatment modalities, and the relationship between radiation oncologists and other members of multidisciplinary teams are vital to facilitate access to high quality cancer treatment for our patients. The evidence base for its application is robust,1 and it incumbent upon all of us involved in radiation oncology to deliver treatment that is of the highest quality and benefit for our patients.

History

Modern radiotherapy is built on the shoulders of giants and has a fascinating and rich history. The radiotherapy treatments that we have available today, with brachytherapy (temporary or permanent implants of radioactive material), radionuclides (ingested or injected isotopes with selective organ uptake) and external beam radiation treatment, have been made possible by committed researchers in the fields of biology, physics, chemistry and clinical medicine over 12 decades, since the discovery of X-rays by Rontgen in 1895, radioactivity by Becquerel in 1896 and radium by Marie Curie in 1898.

Less than three months after Rontgen discovered X-rays, a medical student in Chicago, Emil Grubbe, used X-rays to treat a patient with advanced breast cancer in early 1896, thereby commencing the earliest external beam therapy. As early as the 1920s superficial, and deep, X-ray treatment was available (100-350 Kilovolts). It was soon appreciated that delivering treatment in a number of smaller doses was highly beneficial and facilitated delivery of much higher doses to the cancer, with equivalent or even better normal tissue tolerance. It was not until megavoltage treatment became available that deep seated organs could be effectively treated using external beams of gamma-rays or X-rays. In 1951, cobalt teletherapy units were brought into therapeutic use. In the same year, Lars Leksell proposed the Gamma Knife®. Linear acceleration of electrons to produce high energy x-rays was proposed in 1924 by both Ising and Wilderoe independently.2

The war effort played a major role in the development of the modern linear accelerator. The klystron was developed during the Second World War as a source of microwave power for radars, and the combination of the klystron with linear acceleration led to the development of linear accelerators as we know them today. The first linac came into clinical use in 1953 at the Hammersmith in London.

During 1952, Kaplan and Gintzon developed their first linear accelerator at Stanford and the first patient was treated in their hospital in 1956. Interestingly, they had on-board Kv imaging for field verification and image guided radiotherapy (IGRT) was born.3 During 1956, linear accelerators were commissioned at both Peter MacCallum Cancer Centre and Royal Brisbane and Women’s Hospital by Jake Haimson. Brisbane Hospital’s linac treated the first patient in Australia. By 1962 there were 15 clinical linacs world-wide, three of which were in Australia.4

The technology

Advances in technology have been amazing and have occurred both in a parallel and sequential fashion. Since 1956, the linac has been the workhorse of modern radiotherapy departments. Linacs deliver megavoltage photons (X-rays) and most are also able to deliver electron beams. While the basic method of linear acceleration to produce a beam of X-rays has remained largely unchanged since the 1950s, the capacity to shape and drive the beams during the delivery of treatment has evolved enormously and is now extraordinarily sophisticated. This has been enabled by three critical developments – the advent of multi-leaf collimators, the invention and evolution of computers and major advances in imaging, particularly CT.

Shaping the beam

Since the inception of radiation therapy, shaping the beam to conform more to the treatment shape required has been important. This was initially performed with lead shielding blocks placed between the linac and the patient, and evolved to custom made shielding blocks using low melting point alloys. A revolutionary advance came with the advent of multi-leaf collimators first developed in the 1960s, built into the head of the linacs – tungsten leaves that can be moved during treatment delivery to alter the shape of the treatment beam. Multi-leaf collimators can now be driven remotely and this has facilitated the delivery of complex beam shapes, arc treatment with fields that can even change shape during delivery, and a much faster delivery time despite increasing the number of treatment fields. These beam shaping developments have culminated in greater conformality of the radiation dose, serving to reduce the amount of adjacent normal tissues that receive an unnecessarily high radiation dose.

Computers

The ability to drive the linacs in an increasingly sophisticated manner has been dependent on computers. Computerised planning systems have replaced hand-drawn treatment plans. Furthermore, the ability to incorporate CT images allowed us to map the cancer in three dimensions, thus enabling 3D conformal treatment. More recently, it has become possible through the development of four dimensional (4D) conformal radiation treatment to accommodate the movement that occurs during treatment. The development of inverse planning systems has allowed linacs to not only deliver dose to the target area, but also to modulate the intensity profile of the beam to exclude or restrict dose to organs at risk. Intensity modulated radiation therapy is now considered the standard of care for the radical treatment of cancers in most sites where the limitation of dose to critical organs not requiring treatment is very important for long-term quality of life and survival.5,6

The therapy can be delivered by units with standard linac conformation, or by dedicated helical intensity modulated radiation therapy equipment such as the TomoTherapy machine. The TomoTherapy machine, developed by Mackie, has a compact linac mounted on a rotational gantry and delivers a very large number of beamlets in a rotational fashion, allowing for sophisticated dose sculpting.

Advances in computing also underpin a number of other improvements in radiotherapy techniques. A good example of such an improvement is found in the development of stereotactic radiosurgery and stereotactic radiotherapy. Stereotactic radiosurgery and stereotactic radiotherapy can be used to deliver high doses of radiation to small targets, such as brain metastases, and benign but problematic benign lesions, such as acoustic neuromas and arteriovenous malformations. They can be delivered using a specifically precision engineered linac, or with the TomoTherapy or Gamma Knife® machines. Stereotactic radiosurgery may also be delivered using the CyberKnife.

The ability now to sculpt the dose is exquisite and can be tailored to the clinical situation. However, the potential for marginal miss is greater. Determining the volume to be irradiated requires a meticulous approach and quality assurance of the whole process is critical. Computerised systems allow the interlinkage of clinical information, planning simulators, planning CT scanners, the planning systems and the linacs. A number of failsafe mechanisms have been built in, which are an essential part of the quality integration of RT systems. CT scanning is now available on linacs to correct patient positioning and track day to day organ and tumour changes. MRI-guided linacs are under development in Europe, the US and Australia.

Imaging

Modern imaging has utterly transformed the delivery of radiotherapy. Planning CT scanners form the basis of acquiring the details of a patient’s anatomy for all but the most straightforward treatment plans. The acquisition of volumetric anatomy allows radiation oncologists to map the volume of tissue to be treated and the organs to be excluded or dose limited. All of this information is reconstructed in either three or four dimensions (incorporating motion). Diagnostic CT scans, MRI and functional PET/CT imaging can be fused on to the planning CT scan, facilitating the best possible radiological identification of tumour. Anatomical data acquired with various imaging modalities must then be combined with all known clinical factors and a deep understanding of the natural history of the specific cancer, to enable the final determination of the volume to be treated, the doses and fractionation required and the organs of exclusion to be mapped. Accordingly, radiation oncologists now need to understand CT, PET/CT and MRI anatomy, as well as surface and surgical anatomy. Often identification of the desired target volumes requires input from surgeons, radiologists and PET physicians.

Brachytherapy

By 1900, Danlos had begun brachytherapy treatment at St Louis Hospital in Paris. Brachytherapy using radium was the first curative treatment available for internal tumours, notably cancer of the uterine cervix, with results first published in the 1920s. However, radium is difficult to handle safely and its use results in unwanted whole body patient and operator exposure. Radium has now been replaced by artificial radionuclides such as Caesium137, Iridium192 and Iodine125. The use of these isotopes, with sophisticated afterloading techniques, has eliminated safety concerns and permitted highly conformal dose distributions to be achieved, with major application in the modern day treatment of cervical and prostate cancers. By 1938, artificial radionuclides were used to treat a patient with leukaemia (32P). I131 therapy for differentiated thyroid cancer followed soon after and is now routine.

Particle therapy

Charged subatomic particles have the property of a finite, energy-dependent range in tissues and so offer theoretical dosimetric advantages over X-rays. The most commonly used particles are electrons produced by the same linacs as are used for X-ray therapy. Electrons are most useful in treating relatively superficial tumour volumes because they spare underlying normal tissues.

Heavy particles have also been tested for clinical utility. By 1930, Lawrence developed the first cyclotron at Berkley and by 1945 Wilson had recommended that particles be put to therapeutic use. Initial trials focused on fast neutron therapy based on the anticipated advantage of high LET (densely ionising) radiation in treating hypoxic tumours. However, subsequent radiobiological research showed that the differential sparing of late-reacting normal tissues through dose fractionation of X-ray treatment was lost with high LET beams. Neutron beams (being uncharged) are also much more difficult to shape than X-rays or charged particle beams, resulting in significantly poorer dose distributions. Definitive trials of fast neutron therapy in the 1980s showed no therapeutic advantage with their use.

Attention has since turned to proton therapy, principally based on the precision of dose distribution that can be achieved rather than on any proven radiobiological advantage over ‘standard’ X-rays. The incremental benefit in dose distribution achievable with protons has been significantly narrowed by advances in intensity modulated radiation therapy photon delivery techniques. Accepted indications include some base of skull tumours and paediatric brain tumours because of the reduced risk of late effects on normal tissues. The potential advantage of combining both dosimetric precision and high LET, through the use of heavier charged particles such as carbon ions, is currently being investigated in Japan, Europe and more recently in China.

Radiobiology

From the very beginning of radiotherapy there has been a keen interest in the biological factors that influence the response to ionising irradiation. Bergonie and Tribondeau (1906) were the first to note that fractionating doses of radiation in animal models allowed for the same tissue effect at lower toxicity. From there, Regaud, Coutard and Baclesse pioneered the early clinical work in fractionation. In the early days, when only superficial and orthovoltage X-rays were available, skin toxicity was the limiting factor. Coutard’s recognition of the usefulness of fractionation for decreasing mucositis was a revolutionary observation. From there, many radiation oncologists and biologists have looked for ways to exploit fractionation as a way of maximising the therapeutic ratio between the anti-tumour effect of radiation and damage to dose limiting normal tissues. The differential effects of ionising radiation on cancer and normal tissues is predicated on the classic 4 Rs of radiobiology to describe events occurring between radiation dose fractions: repair of sub-lethal damage; reassortment of the cells within the cell cycle; repopulation of surviving clonogenic cells; and reoxygenation of erstwhile radioresistant hypoxic tumour cells. One of the key radiobiologic discoveries relevant to optimisation of dose fractionation was that late reacting normal tissues were in general, spared to a greater extent than most cancers by dose fractionation. This difference could be modelled by the α ? β ratio in an isoeffect equation which enabled safe changes to fractionation schedules to be made.7 A related pivotal discovery that prolonged overall treatment time increased the risk of recurrence in the treatment of epithelial cancers, notably of the head and neck.8

The benefit of altered fractionation schedules to take advantage of these radiobiological considerations has been demonstrated in a number of randomised clinical trials. Their widespread adoption in Australia is largely limited by resource constraints. With the modern trend to use extremely hypofractionated treatment schedules (low number of fractions) in stereotactic whole body radiation therapy, it must be recognised that no differential sparing of normal tissues within the high dose volume is possible and normal tissue tolerance depends entirely on volume effect – all normal tissues in the high dose volume must be considered expendable, and accordingly every effort is made to physically limit the volume of normal tissue that is irradiated.9

The next major advance in optimisation of radiation dose fractionation schedules is likely to come from molecular genetic characterisation of individual patient’s tumours and normal tissues. While considerable progress has been made in identifying gene mutations or single nucleotide polymorphisms responsible for modulating radiation responses, no predictive assays have yet been developed to the point of clinical application.

Integration of radiation treatment

Radiation oncology is a highly interdisciplinary specialty. Optimum treatment of the majority of cancer patients requires the use of integrated multimodality treatment with various combinations of surgery, radiation and systemic therapies. The Collaboration for Cancer Outcomes Research and Evaluation has developed evidence-based benchmarks for radiotherapy that have provided the basis for the expansion of cancer services in Australia and internationally. The evidence to support the use of radiotherapy has been built on decades of trials and studies, and the methodology to assess this is a disciplined way developed by Delaney and Barton.1 Radiation treatment in some circumstances may be curative as a sole modality, but is very often combined with surgery and drug treatments to maximise both local and systemic cure. Radiation treatment often will allow for less radical surgery (for example in conservative treatment of limb sarcomas and in breast cancer) or may replace surgery (for many people with oropharyngeal cancer). The integration, sequencing and linking of combined modality treatments is important in offering patients the best possible care. Over 80% of the indications for radiotherapy are for the improvement of cure or the increase of survival.10

Advocacy

Radiotherapy is a cornerstone of cancer care with deep and historical science and amazing technology supporting it. These attributes are vital, however the overall care of people with cancer drives radiation oncologists first and foremost and underpins our approach to multidisciplinary care.

The Faculty of Radiation Oncology, Royal Australian and New Zealand College of Radiologists (RANZCR), has advocated on behalf of cancer patients since its inception, emphasising the need to close the gap for people with cancer in accessing cancer care in general and radiation treatment in particular. In 2000, together with the Australian Institute of Radiography and the Australasian College of Physicists, Scientist and Engineers in Medicine, the Tripartite Committee was formed. The committee is a shining example of goodwill and multidisciplinary cooperation and its output has had a major influence in Australia and New Zealand in raising awareness of the need for high quality treatment and the shortfalls in physical and staffing infrastructure. The Tripartite committee developed the National Strategic Plan for Australia in 2000, and has recently published a new plan ‘Planning for the best: Tripartite National Strategic Plan for Radiation Oncology 2012 -2022’, which makes recommendations for changes required to optimise all aspects of radiation oncology for Australian cancer patients.11 It also developed the Quality Standards for Radiation Treatment Delivery, which were released in 2011.12

The rigour for our radiation oncology trainees is high and the RANZCR was among the first of the professional colleges to be accredited by the Australian Medical Council. The college has since undergone extensive review and taken advice from professional educators in modifying its training and assessment programs.

Quality

The quality standards developed by the Tripartite Committee form the quality base in Australia and New Zealand. Delivering quality treatment is highly complex, and time consuming, but essential. Daily, weekly, monthly and annual quality assurance is an ordinary part of treating departments.13 The need for participation in clinical trials and to keep accurate recording of short and long-term data cannot be underestimated.

The Trans Tasman Radiation Oncology Group (TROG) and other international trials groups require quality assurance for the majority of trials. This often requires assessment of the entire treatment chain and is a costly part of clinical trial activity. The requirement however, is high. One of, if not the most important trial ever conducted was the TROG 02.02 or HeadSTART Trial. Although the trial was asking a question regarding the addition of an hypoxic cell cytotoxin, quality assurance and real time review of treatment plans was required. The trial demonstrated that inferior quality head and neck radiotherapy resulted in a 24% deficit in locoregional control and a 20% deficit in overall survival at two years.14 The quality of the radiotherapy dominated the drug question, putting in question all trials where quality assurance of the radiotherapy was not integral.

The future

The possibilities for radiation oncology are extraordinary. By understanding and building on the depth of developments to date, and having a clear understanding of what outcomes we are looking for – be they relief of symptoms, increased cure or a reduction in side-effects, or all three, collaboration will achieve our goals more quickly. Unfettered technology development by our clinicians, radiation physicists and engineers, continuing advances in our understanding of tumour biology and predictive assays, and the interaction of radiation with drugs and other molecules, increasing dose to improve local cure, altering the distribution of dose within cancer tissue depending on biological markers of resistance or sensitivity, monitoring change occurring through treatment with functional MRI or PET imaging using novel tracers and altering and adapting the dose accordingly – all of these are tantalising possibilities. Overt cooperation and collaboration from many will be required to see this through.

Currently many factors improve patient outcomes, both in terms of cure and quality of life. Making evidence-based and sensible recommendations upfront as to where and when to have radiation treatment may be of benefit, as will having clinicians and patients choose appropriately linked and sequenced care, and when radiation treatment is used, delivering high quality treatment.